Nucleus paragigantocellularis afferents in male and female rats: Organization, gonadal steroid receptor expression, and activation during sexual behavior

Normandin, Joseph J.; Murphy, Anne Z.

doi:10.1002/cne.21704

Cited by 36 publications

(26 citation statements)

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“…The regulation of these phases is mediated by various central nervous systems structures. The medial preoptic area of the hypothalamus is involved in the control of libido and ejaculation, the locus coeruleus in the mediation of sexual arousal, and the nucleus paragigantocellularis and the paraventricular nucleus of hypothalamus in ejaculation control (17)(18)(19)(20). Interestingly, the ERβ protein is detectable in the preoptic area, the paraventricular nucleus of the hypothalamus, the dorsal raphe, and locus coeruleus (21,22).…”

Section: Discussionmentioning

confidence: 99%

Estrogen dependent activation function of ERβ is essential for the sexual behavior of mouse females

Antal

Petit-Demoulière

Méziane

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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We previously generated and characterized a genuine estrogen receptor (ER) β-null mouse line (named ERβ ST L−/L− ) and showed that ERβ ST L−/L− mice were sterile, due to an ovulation impairment in females and to an unknown reason in males, as their reproductive organs and spermatozoid motility appeared normal. We report here an assessment of the sexual behavior of ERβ ST L−/L− null mice. We found that ERβ ST L−/L− males display mildly impaired sexual behavior and that ERβ ST L−/L− females are significantly less receptive and less attractive than wild-type (WT) females. Decreased attractivity is also exhibited by ERβAF2 0 but not by ERβAF1 0 mutant females (females devoid of either AF2 or AF1 activation function of ERβ). Interestingly, by using an odor preference test, we have determined that the low attractiveness of ERβ ST L−/L− and ERβAF2 0 females is related to a deficiency of a volatile chemosignal.T he role of estradiol (E2) and estrogen receptor α (ERα) on the sexual behavior of the mouse is well known (1). ERα-null females do not display sexual receptivity, although they are as sexually attractive as wild-type (WT) controls. ERα-null males exhibit severely reduced numbers of mounts, thrusts and intromissions, and very few ejaculate (2). In contrast, ERβ has not yet been reported to play an important role in mouse sexual behavior (3). Several mouse lines bearing partial null mutations of ERβ have been generated and named according to the laboratory of origin (4, 5): ERβKO CH originated from a Chapel Hill laboratory (6), ERβKO ST from a Strasbourg laboratory (7), and ERβKO WY from Wyeth (8). The ERβKO CH line has been duplicated and a second colony, named ERβKO KI , has been established at the Karolinska Institut (9). A study performed on ERβKO CH males and females showed that they performed normally in sexual behavior tests. Nevertheless, a delay in the age of the first ejaculation was reported in these mice, without further consequences in adults (10), as adults ERβKO CH males were fertile and sired litters with the same efficiency as their WT counterparts (3). Contrasting with an apparent minor role in sexual behavior, ERβ appeared to be a major determinant of antianxiety behaviors in female mice (11,12), and, in a transient manner, of aggressive behaviors in male mice (13). ERβ was also reported to be involved in male mouse brain defeminization (14).We recently reported the generation and characterization of a complete ERβ-null mouse, the ERβ ST L−/L− mouse, of which the morphological phenotype contrasts in many aspects with that of the described ERβKO KI mutant (5). ERβ ST L−/L− females were sterile, due to ovulation impairment, and males exhibited infertility from an unknown reason because their internal and external reproductive organs appeared morphologically normal. Because ERβ ST L−/L− mice of both sexes displayed reproductive anomalies, we performed sex behavioral tests to evaluate the extent of ERβ involvement in mouse reproductive functions. We found that ERβ is required for a normal sexual beh...

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Section: Discussionmentioning

confidence: 99%

Estrogen dependent activation function of ERβ is essential for the sexual behavior of mouse females

Antal

Petit-Demoulière

Méziane

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…The nPGi receives projections from upstream sites related to sexual behavior, including the paraventricular nucleus of the hypothalamus, medial preoptic area, and periaqueductal gray (Murphy and Hoffman, 2001; Murphy et al, 1999; Normandin and Murphy, 2008), and in turn, projects to the spinal motoneurons (pudendal motoneurons) innervating the bulbospongiosus and ischiocavernosus muscles (Hermann et al, 2003; Marson and Carson 3rd, 1999; Marson and McKenna, 1996; Tang et al, 1999), which are critical for ejaculation in male rats (Miura et al, 2001; Pescatori et al, 1993) and humans (Hsu et al, 2004; Shafik et al, 2009). …”

Section: Introductionmentioning

confidence: 99%

Serotonergic lesions of the periaqueductal gray, a primary source of serotonin to the nucleus paragigantocellularis, facilitate sexual behavior in male rats

Normandin

Murphy

2011

Pharmacology Biochemistry and Behavior

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While selective serotonin reuptake inhibitors (SSRIs) are widely used to treat anxiety and depression, they also produce profound disruptions of sexual function including delayed orgasm/ ejaculation. The nucleus paragigantocellularis (nPGi), a primary source of inhibition of ejaculation in male rats, contains receptors for serotonin (5-HT). The ventrolateral periaqueductal gray (vlPAG) provides serotonin to this region, thus providing an anatomical and neurochemical basis for serotonergic regulation of the nPGi. We hypothesize that 5-HT acting at the nPGi could underlie the SSRI-induced inhibition of ejaculation in rodents. To this end, we produced 5-HT lesions of the source of 5-HT to the nPGi (the vlPAG) and examined sexual behavior. Removing the source of 5-HT to the nPGi facilitated genital reflexes, but not other aspects of sexual behavior, consistent with our hypothesis. Namely, 5-HT lesions produced a significant increase in the mean number of ejaculations and a significant decrease in ejaculation latency as compared to sham lesioned animals, while latency to mating and the post-ejaculatory interval did not differ. These data suggest that the serotonergic vlPAG-nPGi pathway is an important regulatory mechanism for the inhibition of ejaculation in rats, and supports the hypothesis that this circuit contributes to SSRI-induced inhibition of ejaculation.

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“…The activity of an nPGi homologue in humans could account for such dysregulation if activity in this region is abnormally regulated. For example, brain regions associated with anxiety in humans and non-human animals, such as the central amygdala (McEwen, 2007), project to the nPGi (Normandin and Murphy, 2008) providing a mechanism whereby psychological stress, often noted in ejaculatory disorders in men (McCabe et al, 2010, Rowland et al, 2010) and in female sexual dysfunction (Clayton and Hamilton, 2010, McCabe et al, 2010), could affect nPGi regulation of genital reflexes. In addition, selective serotonin reuptake inhibitors, commonly prescribed for depression (Arroll et al, 2009, Koenig and Thase, 2009), appear to increase inhibition of ejaculation in men (Kennedy and Rizvi, 2009, Schweitzer et al, 2009) which could in part be mediated by the serotonergic neurons of the nPGi (Marson and McKenna, 1992) or its targets (2007).…”

Section: 0 Discussionmentioning

confidence: 99%

“…Males engaged in non-paced mating with a non-experimental stimulus female as previously described (Normandin and Murphy, 2008). Female sexual behavior was conducted using a paced mating arena in which a divider containing two 4cm diameter holes through which only the females could pass was placed in the last 1/3 of the arena.…”

Section: Methodsmentioning

confidence: 99%

“…Retrograde trans-synaptic tracing from the rat clitoris (Marson and Murphy, 2006), vagina (Marson and Murphy, 2006), and cervix (Lee and Erskine, 2000) produces labeling in the nPGi at time points consistent with a direct monosynaptic projection from the nPGi to the motoneurons controlling the genital musculature. In addition, a number of brain regions associated with sexual behavior send direct projections to the nPGi in females (Murphy and Hoffman, 2001, Marson and Foley, 2004, Marson and Murphy, 2006, Normandin and Murphy, 2008), further suggesting a role for the nPGi in female sexual behavior.…”

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confidence: 99%

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Excitotoxic lesions of the nucleus paragigantocellularis facilitate male sexual behavior but attenuate female sexual behavior in rats

Normandin

Murphy

2011

Neuroscience

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Little is known regarding the descending inhibitory control of genital reflexes such as ejaculation and vaginal contractions. The brainstem nucleus paragigantocellularis (nPGi) projects bilaterally to the lumbosacral motoneuron pools that innervate the genital musculature of both male and female rats. Electrolytic nPGi lesions facilitate ejaculation in males, leading to the hypothesis that the nPGi is the source of descending inhibition to genital reflexes. However, the function of the nPGi in female sexual behavior remains to be elucidated. To this end, male and female rats received bilateral excitotoxic fiber-sparing lesions of the nPGi, and sexual behavior and sexual behavior-induced Fos expression were examined. In males, nPGi lesions facilitated copulation, supporting the hypothesis that the nPGi, and not fibers-of-passage, is the source of descending inhibition of genital reflexes in male rats. nPGi lesions in males did not alter sexual behaviorinduced Fos expression in any brain region examined. nPGi-lesioned females spent significantly less time mating with stimulus males and had significantly longer ejaculation-return latencies compared to baseline. These results did not significantly differ from control females, but this trend warranted further analysis of the reinforcing value of sexual behavior. Both lesioned and nonlesioned females formed a conditioned place preference (CPP) for artificial vaginocervical stimulation (aVCS). However, post-reinforcement, nPGi-lesioned females did not differ in the percentage of time in spent in the non-reinforced chamber versus the reinforced chamber, suggesting a weakened CPP for aVCS. nPGi lesions in females reduced sexual behavior-induced Fos expression throughout the hypothalamus and amygdala. Taken together, these results suggest that while nPGi lesions in males facilitate copulation, such lesions in females attenuate several aspects of sexual behavior resulting in a reduction in the rewarding value of copulation that may be mediated by nPGi control of genital reflexes. This work has important implications for the understanding and treatment of sexual dysfunction in people including delayed/premature ejaculation, involuntary vaginal spasms, and pain during intercourse.Correspondence to: Anne Z. Murphy, Ph.D., Neuroscience Institute, Georgia State University, PO Box 5030, Atlanta, amurphy@gsu.edu, Phone: 404.413.5332, Fax: 404.413.5301. 1 Present address: Netherlands Institute for Neuroscience, Neuroendocrinology Group, Meibergdreef 47, 1105 BA, Amsterdam, The Netherlands, j.normandin@nin.knaw.nl Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that a...

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Nucleus paragigantocellularis afferents in male and female rats: Organization, gonadal steroid receptor expression, and activation during sexual behavior

Cited by 36 publications

References 81 publications

Estrogen dependent activation function of ERβ is essential for the sexual behavior of mouse females

Estrogen dependent activation function of ERβ is essential for the sexual behavior of mouse females

Serotonergic lesions of the periaqueductal gray, a primary source of serotonin to the nucleus paragigantocellularis, facilitate sexual behavior in male rats

Excitotoxic lesions of the nucleus paragigantocellularis facilitate male sexual behavior but attenuate female sexual behavior in rats

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